Relevance to NIAID Mission: The research detailed in this proposal will allow Dr. Mary S. Campbell, under the mentorship of Dr. James I. Mullins and Dr. Geoffrey S. Gottlieb and with collaborators at the University of Washington and the University of Dakar, Senegal, to acquire the technical and analytical skills that will foster her development into a productive, innovative physician-scientist. Background: Since the first cases that were recognized in the early 1980s, the number of people infected with human immunodeficiency virus type-1 (HIV-1) has continued to increase throughout the world. Despite many advances in our understanding of the mechanisms of viral pathogenesis and our ability to treat infected individuals through effective pharmacologic therapies, methods to avert viral infection have been largely unsuccessful. The events surrounding the transmission of HIV at the mucosal interface remain incompletely understood. Primary Hypothesis: Exposure to HIV-1 at the mucosal surface more frequently leads to infection that remains localized in the mucosa rather than progressing to a systemic infection. Research Design and Methods: Blood and mucosal specimens from several previously-established longitudinal cohorts of HIV-1 infected individuals in Seattle, Washington and in Dakar, Senegal are available for this study. Based upon extensive behavioral survey data, it has been established that these individuals are at high risk for acquisition of additional HIV-1 strains. In this project, HIV-1 sequences will be isolated from both blood and mucosal specimens from each subject. The viral sequences will then be analyzed using phylogenetic methods in order to determine the relatedness between viral strains in the mucosa and those present in blood. This will help elucidate the frequency with which mucosal exposure to viral strains leads to the localized mucosal infection versus establishment of systemic HIV-1 infection. Relevance to Public Health: The research planned in this proposal will provide insight into fundamental questions regarding the mechanism by which HIV-1 infection becomes established after exposure at the mucosal surface, the predominant mode of transmission worldwide. These observations may be of significant importance to the development of HIV vaccines and microbicides.